Age-related decline in human immune response is marked by the accumulation of CD28- CD8 T cells that is attributed to repeated antigenic stimulation and to homeostatic proliferation mediated by cytokines such as IL-15. However, the identity of cytokines that are responsible for the maintenance of CD28 expression is less known. Here we report the role of IL-21 in regulation of IL-15-mediated growth and CD28 expression of CD8 memory T cells from young and old donors. We showed that IL-21 drives more IL-15-stimulated cells to enter cell division and to undergo apoptosis. Furthermore, IL-21 preferentially enhanced IL-15-induced proliferation of CD28+ CD8 memory T cells over their CD28- counterpart because CD28+ cells expressed higher levels of IL-15 and IL-21 receptors and greater phosphorylation of STAT5 upon IL-15 and IL-21 stimulation. In addition, IL-21 also reduced IL-15-induced CD28 down-regulation in CD8 memory T cells. Finally, the ability of proliferation and survival in response to homeostatic cytokines IL-15 and IL-21 of nave (CD45RA+CD28+) and CD28- CD8 T cells but not memory (CD45RA-CD28+) CD8 T cells decreased with age. Together, these findings suggest that IL-21 serves as an antagonist to the IL-15-induced increase of CD28- CD8 T cells and may play a role in age-associated changes of CD8 T cell homeostasis and function.